Biochemical Markers in the Prediction of Pregnancy Outcome in Gestational Diabetes Mellitus.

Background and Objectives: Gestational diabetes mellitus (GDM) may impact both maternal and fetal/neonatal health. The identification of prognostic indicators for GDM may improve risk assessment and selection of patient for intensive monitoring. The aim of this study was to find potential predictors of adverse pregnancy outcome in GDM and normoglycemic patients by comparing the levels of different biochemical parameters and the values of blood cell count (BCC) between GDM and normoglycemic patients and between patients with adverse and good outcome. Materials and Methods: Prospective clinical study included 49 patients with GDM (study group) and 44 healthy pregnant women (control group) who underwent oral glucose tolerance test (OGTT) at gestational age of 24-28 weeks. At the time of OGTT peripheral blood was taken for the determination of glucose levels, insulin, glycated hemoglobin, lipid status, homeostatic model assessment, BCC, iron and zinc metabolism, liver function, kidney function and inflammatory status. Each group was divided into two subgroups-normal and poor pregnancy outcome. Results: Higher RBC, hemoglobin concentration, hematocrit value, fasting glucose, uric acid and fibrinogen were found in GDM patients compared to control group. In GDM patients with poor pregnancy outcome values of fibrinogen, ALT, sedimentation rate, granulocyte and total leukocyte counts were elevated, while the serum level of zinc was significantly lower. Higher level of fibrinogen was found in normoglycemic patients with adverse pregnancy outcomes. ROC curve was constructed in order to assess fibrinogen's biomarker potential. The established AUC value for diagnostic ROC was 0.816 (p < 0.001, 95% CI 0.691-0.941), while the AUC value for assessing fibrinogen's potential to predict poor pregnancy outcome in GDM was 0.751 (p = 0.0096, 95% CI 0.561-0.941). Conclusions: The results of our study demonstrated that the best prognostic potential in GDM showed inflammation related parameters, identifying fibrinogen as a parameter with both diagnostic and prognostic ability.

Diagnostic properties of miR-146a-5p from liquid biopsies in prostate cancer: A meta-analysis.

BACKGROUND: Several studies on biomarker properties of microRNAs from liquid biopsy in prostate cancer (PCa) identified miR-146a-5p as a potential novel diagnostic marker. However, other studies with the same or similar topic failed to confirm the supposed discriminatory ability of miR-146a-5p, for which reason we aimed at elucidating the potential biomarker role of circulatory/urinary miR-146a-5p in PCa by conducting a qualitative and quantitative data synthesis. METHODS: Eligible articles were identified by searching PubMed, Scopus and Web of Science databases. Open MetaAnalyst software was used for pooling data on sensitivity, specificity, likelihood ratio and diagnostic odds ratio (OR) of miR-146a-5p. RESULTS: A total of 15 articles were eligible for qualitative data synthesis, while the results from 13 studies with 2080 participants were included in the meta-analysis. The established between-study heterogeneity was high, while the expression of hsa-miR-146a was associated with a diagnostic OR of 3.544 (P < 0.001; 95 %CI 2.186-5.747). Pooled sensitivity was found to be lower than 70 % (0.655, 95 %CI 0.573-0.729, P < 0.001), while the obtained value for specificity was 65 % (95 %CI 0.583-0.709, P < 0.001). Segregating studies according to ethnicity, sample type or the type of controls did not result in significantly higher sensitivity and specificity in subgroups, compared to the overall pooled data. CONCLUSIONS: The resulting pooled sensitivity, specificity and diagnostic OR do not qualify miR-146a-5p for a reliable diagnostic biomarker of PCa.

Glycosylation and Characterization of Human Transferrin in an End-Stage Kidney Disease.

Chronic kidney disease (CKD) is a global health concern affecting approximately one billion individuals worldwide. End-stage kidney disease (ESKD), the most severe form of CKD, is often accompanied by anemia. Peritoneal dialysis (PD), a common treatment for ESKD, utilizes the peritoneum for solute transfer but is associated with complications including protein loss, including transferrin (Tf) a key protein involved in iron transport. This study investigated Tf characteristics in ESKD patients compared to healthy individuals using lectin microarray, spectroscopic techniques and immunocytochemical analysis to assess Tf interaction with transferrin receptors (TfRs). ESKD patients exhibited altered Tf glycosylation patterns, evidenced by significant changes in lectin reactivity compared to healthy controls. However, structural analyses revealed no significant differences in the Tf secondary or tertiary structures between the two groups. A functional analysis demonstrated comparable Tf-TfR interaction in both PD and healthy samples. Despite significant alterations in Tf glycosylation, structural integrity and Tf-TfR interaction remained preserved in PD patients. These findings suggest that while glycosylation changes may influence iron metabolism, they do not impair Tf function. The study highlights the importance of a glucose-free dialysis solutions in managing anemia exacerbation in PD patients with poorly controlled anemia, potentially offering a targeted therapeutic approach to improve patient outcomes.

Association between nitric oxide synthase (NOS3) gene polymorphisms and diabetic nephropathy: An updated meta-analysis.

Polymorphisms located within NOS3 gene have been investigated as susceptibility variants for diabetic nephropathy (DN) in type 2 diabetes mellitus (T2DM) in a large number of studies. However, these previous articles yielded inconsistent results and we aimed at elucidating the impact of NOS3 variants on DN risk in T2DM by conducting an updated systematic data synthesis. A total of 36 studies (12,807 participants) were selected for qualitative data synthesis, while 33 records with 11,649 subjects were included in the meta-analysis. The pooled analysis demonstrated the association of minor alleles of rs2070744 and rs1799983 with an increased susceptibility to DN (P < 0.001 and P = 0.015 for allelic model, respectively). For both of these variants, a significant effect of subgrouping according to ethnicity was found. Rs869109213 displayed an association with DN susceptibility, with pooled effect measures indicating a predisposing effect of the minor allele a (Prec = 0.002, ORrec = 1.960, 95%CI 1.288-2.983; Paavs. bb = 0.001, ORaavs. bb = 2.014, 95%CI 1.316-3.083). These findings support the effects of NOS3 variants on the risk of developing DN in T2DM.

Significance of 1,25-Dihydroxyvitamin D3 on Overall Mortality in Peritoneal Dialysis Patients with COVID-19.

In previous publications, we pointed out the importance of mannosylation of fibrinogen for the development of cardiovascular complications and fucosylation as a predictor of peritoneal membrane dysfunction in patients on peritoneal dialysis (PD). After a follow-up period of 30 months from the onset of the COVID-19 pandemic, we evaluated the significance of 1,25-dihydroxyvitamin D3 (calcitriol) therapy, primary disease, biochemical and hematologic analyzes, and previously performed glycan analysis by lectin-based microarray as predictors of mortality in this patient group. After univariate Cox regression analysis, diabetes mellitus (DM) and calcitriol therapy were found to be potential predictors of mortality. Additional multivariate Cox regression analysis confirmed that only DM was a predictor of mortality. Nevertheless, the use of calcitriol in therapy significantly reduced mortality in this patient group, as shown by the Kaplan-Meier survival curve. The presence of DM as a concomitant disease proved to be a strong predictor of fatal outcome in PD patients infected with SARS-CoV-2. This is the first study to indicate the importance and beneficial effect of calcitriol therapy on survival in PD patients with COVID-19 infection. In addition, this study points to the possibility that adverse thrombogenic events observed in PD patients during the pandemic may be caused by aberrant fibrinogen glycosylation.

Food Antioxidants and Their Interaction with Human Proteins.

Common to all biological systems and living organisms are molecular interactions, which may lead to specific physiological events. Most often, a cascade of events occurs, establishing an equilibrium between possibly competing and/or synergistic processes. Biochemical pathways that sustain life depend on multiple intrinsic and extrinsic factors contributing to aging and/or diseases. This article deals with food antioxidants and human proteins from the circulation, their interaction, their effect on the structure, properties, and function of antioxidant-bound proteins, and the possible impact of complex formation on antioxidants. An overview of studies examining interactions between individual antioxidant compounds and major blood proteins is presented with findings. Investigating antioxidant/protein interactions at the level of the human organism and determining antioxidant distribution between proteins and involvement in the particular physiological role is a very complex and challenging task. However, by knowing the role of a particular protein in certain pathology or aging, and the effect exerted by a particular antioxidant bound to it, it is possible to recommend specific food intake or resistance to it to improve the condition or slow down the process.

Interdisciplinary care in orbital complications of acute rhinosinusitis in children.

Purpose: Orbital cellulitis is a serious condition with potentially severe complications. Treatment requires interdisciplinary care and early introduction of antimicrobial therapy. In our tertiary center, a team of pediatricians, pediatric ophthalmologists, and otorhinolaryngologists successfully participated in the management of pediatric periorbital/orbital cellulitis. This study aimed to demonstrate our interdisciplinary approach and to investigate clinical profile and management of pediatric periorbital/orbital cellulitis. Methods: A retrospective chart review was performed of all pediatric patients hospitalized for periorbital and orbital cellulitis in a tertiary hospital center from September 15, 2016, to March 15, 2020. Results: A total of 26 children-median age 2.7 years (range 0.5-12)-were treated during the study period. Disease presentation was unilateral, mainly during winter (n = 12) and autumn (n = 12), without ophthalmoplegia/proptosis. Seven patients had orbital cellulitis (Chandler classification of ≥III) and were older (6.5 years, P = 0.011) with sinusitis (P < 0.001), required surgery (P = 0.004), underwent longer antimicrobial treatment (13 days, P < 0.001), and had a longer length of hospital stay (13.43 days, P = 0.001). Orbital cellulitis occurred in a median of three days (range 1-12) of acute rhinosinusitis. Radiological survey was performed in 11 patients, whereas six patients were treated surgically. All intraoperatively collected cultures (sinus swabs) were positive, whereas Streptococcus pyogenes and Peptostreptococcus were isolated in five cases. All patients fully recovered. No recurrence was documented. Conclusion: Sinusitis is associated with severe orbital cellulitis and surgical management. Orbital cellulitis occurred early in the course of acute rhinosinusitis, as a distinctive presentation of rhinosinusitis. Interdisciplinary care and early management are crucial in treatment of pediatric periorbital/orbital cellulitis.

The association of human leucocyte antigen (HLA) alleles with COVID-19 severity: A systematic review and meta-analysis.

Due to their pivotal role in orchestrating the immune response, HLA loci were recognized as candidates for genetic association studies related to the severity of COVID-19. Since the findings on the effects of HLA alleles on the outcome of SARS-CoV-2 infection remain inconclusive, we aimed to elucidate the potential involvement of genetic variability within HLA loci in the molecular genetics of COVID-19 by classifying the articles according to different disease severity/outcomes and by conducting a systematic review with meta-analysis. Potentially eligible studies were identified by searching PubMed, Scopus and Web of Science literature databases. A total of 28 studies with 13,073 participants were included in qualitative synthesis, while the results of 19 studies with 10,551 SARS-CoV-2-positive participants were pooled in the meta-analysis. According to the results of quantitative data synthesis, association with COVID-19 severity or with the lethal outcome was determined for the following alleles and allele families: HLA-A*01, HLA-A*03, HLA-A*11, HLA-A*23, HLA-A*31, HLA-A*68, HLA-A*68:02, HLA-B*07:02, HLA-B*14, HLA-B*15, HLA-B*40:02, HLA-B*51:01, HLA-B*53, HLA-B*54, HLA-B*54:01, HLA-C*04, HLA-C*04:01, HLA-C*06, HLA-C*07:02, HLA-DRB1*11, HLA-DRB1*15, HLA-DQB1*03 and HLA-DQB1*06 (assuming either allelic or dominant genetic model). We conclude that alleles of HLA-A, -B, -C, -DRB1 and -DQB1 loci may represent potential biomarkers of COVID-19 severity and/or mortality, which needs to be confirmed in a larger set of studies.

The Insulin-like Growth Factor System and Colorectal Cancer.

Insulin-like growth factors (IGFs) are peptides which exert mitogenic, endocrine and cytokine activities. Together with their receptors, binding proteins and associated molecules, they participate in numerous pathophysiological processes, including cancer development. Colorectal cancer (CRC) is a disease with high incidence and mortality rates worldwide, whose etiology usually represents a combination of the environmental and genetic factors. IGFs are most often increased in CRC, enabling excessive autocrine/paracrine stimulation of the cell growth. Overexpression or increased activation/accessibility of IGF receptors is a coinciding step which transmits IGF-related signals. A number of molecules and biochemical mechanisms exert modulatory effects shaping the final outcome of the IGF-stimulated processes, frequently leading to neoplastic transformation in the case of irreparable disbalance. The IGF system and related molecules and pathways which participate in the development of CRC are the focus of this review.

The association of ACE1, ACE2, TMPRSS2, IFITM3 and VDR polymorphisms with COVID-19 severity: A systematic review and meta-analysis.

Genes involved in the regulation of viral recognition and its entry into a host cell have been identified as candidates for genetic association studies on COVID-19 severity. Published findings on the effects of polymorphisms within ACE1, ACE2, TMPRSS2, IFITM3 and VDR genes remained inconclusive, so we conducted a systematic review and meta-analysis in order to elucidate their potential involvement in the genetic basis underlying the severity of COVID-19 and/or an outcome of SARS-CoV-2 infection. Identification of potentially eligible studies was based on PubMed, Scopus and Web of Science database search. Relevant studies (n=29) with a total number of 8247 SARS-CoV-2-positive participants were included in qualitative synthesis, while results of 21 studies involving 5939 were pooled in meta-analysis. Minor allele I of rs1799752 located within ACE1 was identified as a protective variant against severe COVID-19, while its effect on mortality rate was opposite. Similarly, minor allele A of ACE2 polymorphism, rs2285666, was found to associate with a decreased risk of severe COVID-19 (P = 0.003, OR = 0.512, 95 % CI = 0.331-0.793). Statistical significance was also seen for the association between COVID-19 severity and rs12329760 located within TMPRSS2. Our results did not support the supposed association of rs12252 in IFITM3 and polymorphisms within VDR with disease severity. We conclude that genetic variants within ACE1, ACE2 and TMPRSS2 may be potential biomarkers of COVID-19 severity, which needs to be further confirmed in a larger set of studies.

Albumin at the intersection between antioxidant and pro-oxidant in patients on peritoneal dialysis.

Albumin (HSA) is a multifunctional protein and due to its free Cys34 thiol group, represents a main source of free thiols in the circulation. This property of HSA, combined with its ability to sequester redox active Cu(II) ions, makes HSA a dominant circulatory antioxidant. End stage kidney disease (ESRD) is a condition accompanied by elevated oxidative stress. The aim of the present study was to examine changes in the antioxidative capacity of HSA and Cu(II) binding affinity in patients on peritoneal dialysis (PD), and relate it to the Cys34 thiol group content and other structural changes of this molecule. HSA molecules are modified in ESRD patients subjected to PD, having significantly lower thiol group and bound Cu(II) content, reduced antioxidant capacity, an increased content of advanced glycation end-products and altered conformation. Also, Cu(II) binding capacity of HSA in these patients is impaired, since a significant portion of the high-affinity metal-binding site is unable to interact with Cu(II). Taking into account that the concentration of Cu(II) in the circulation of ESRD patients is much higher than in healthy persons and that Cu(II) binding capacity of HSA in these patients is significantly impaired, HSA may be considered as a novel circulatory pro-oxidant, thus exacerbating oxidative stress.

Major trace elements and their binding proteins in the early phase of Covid-19 infection.

Metal ions seem to play important roles in the pathogenesis of the novel coronavirus disease of 2019 (Covid-19) and are under investigation as potential prognostic markers and supplements in therapeutic procedures. The present study was aimed at assessing the relationship between the most abundant essential microelements (iron, zinc and copper) and their major binding proteins in the circulation in the early stage of infection. The concentration of zinc ions was measured to be higher in infected than in healthy persons, as well as ratios zinc/albumin and zinc/alpha-2-macroglobulin. Increased zinc levels could be attributed to cellular redistribution of zinc ions or to a use of zinc supplementation (zinc concentration was above the upper reference limit in one-third of infected individuals). Immunoblot analysis of protein molecular forms revealed that infected persons had greater amounts of proteinase-bound alpha-2-macroglobulin tetramer and albumin monomer than healthy individuals. The quantities of these forms were correlated with the concentration of zinc ions (r = 0.42 and 0.55, respectively) in healthy persons, but correlations were lost in infected individuals, most likely due to very high zinc concentrations in some participants which were not proportionally followed by changes in the distribution of protein species. Although we still have to wait for a firm confirmation of the involvement of zinc in beneficial defense mechanisms in patients with Covid-19, it seems that this ion may contribute to the existence of circulating protein forms which are the most optimal.

UNILATERAL VS. DIFFUSE CHRONIC RHINOSINUSITIS.

Chronic rhinosinusitis (CRS) is a widespread disease with various symptoms. It is defined as an inflammation of the nasal mucosa and paranasal sinuses lasting for 12 weeks, with symptoms of nasal obstruction and/or congestion and facial pain and/or pressure as well as decreased sense of smell. Despite the widespread prevalence of the disease, the diagnosis and treatment of CRS are still not adequately developed, so many patients remain misdiagnosed. This study involved 150 patients who, according to EPOS guidelines, met the diagnosis of CRS without nasal polyposis. Each patient underwent a computerized tomography (CT) scan of the paranasal sinuses, which was evaluated according to the Lund-Mackay scoring system. Furthermore, patients completed a visual analog scale (VAS) score questionnaire which examined the severity of their symptoms. The aim of this study was to find an association between the degree of mucositis and the clinical symptoms reported by the patient. Our results showed a low positive correlation between nasal secretion and Lund-Mackay score for the bilateral ostiomeatal complex (OMC). Furthermore, a low positive correlation was found between the severity of reduced sense of smell and severity of anterior ethmoid and sphenoid sinusitis. The results demonstrated a low negative correlation between the severity of facial pain or pressure and the severity of inflammation of the anterior ethmoid and sphenoid sinus. The results of statistical testing did not show statistical differences in severity of subjective symptoms for almost all of the observed symptoms in persons with unilateral inflammation and persons without unilateral inflammation, except for cough. People who did not have unilateral inflammation had a more pronounced cough compared with people who had unilateral inflammation. However, these correlations were very mild and not clinically significant, so we cannot say that the distribution of sinusitis significantly affects the occurrence of characteristic symptoms in chronic rhinosinusitis.

DOES THE TYPE OF SURGERY IN BRAIN ABSCESS PATIENTS INFLUENCE THE OUTCOME? ANALYSIS BASED ON THE PROPENSITY SCORE METHOD.

There are different options for surgical treatment of brain abscess, mainly standard craniotomy and stereotactic aspiration. It has not yet been established which of these options is associated with a more favorable outcome under similar baseline conditions of patients. Demographic characteristics, microbiology, clinical presentation, and treatment outcome were analyzed for surgically treated adult patients with brain abscess over a 14-year period. A propensity score model was applied to account for baseline conditions that may determine the choice of neurosurgical method. The propensity score was included in the prediction of a favorable outcome, defined as a Glasgow Outcome Scale (GOS) score 4 or 5. We analyzed 91 adult surgically treated patients, of which 53 had standard craniotomy and 38 stereotactic aspiration of brain abscess. Focal neurological deficit was the most common symptom present in 60 (65.9%) patients on admission. Sixty-seven (73.6%) patients had GOS 4 or 5, and seven (7.7%) patients died. The choice of surgery did not influence the outcome (OR 1.181, 95% CI 0.349-3.995), neither did the time elapsed from diagnosis to surgery (OR 0.998, 95% CI 0.981-1.015). Propensity towards standard craniotomy procedure did not influence outcome in brain abscess patients (OR 1.181, 95% CI 0.349-3.995). Worse outcome (GOS below 4) was independently associated with Glasgow Coma Score (GCS) on admission (OR 0.787, CI 0.656-0.944). The choice of neurosurgical procedure did not influence the outcome in patients with brain abscess. Patients with brain abscess who had lower GCS on admission also had worse outcome.

Fibrinogen Fucosylation as a Prognostic Marker of End-Stage Renal Disease in Patients on Peritoneal Dialysis.

Glycosylation may strongly affect protein structure and functions. A high risk of cardiovascular complications seen in patients with end-stage renal disease (ESRD) is, at least partly associated with delayed clot formation, increased clot strength, and delayed cloth lysis. Taking into consideration that fibrinogen mediates these processes, we isolated fibrinogen from the plasma from patients with ESRD on peritoneal dialysis (ESRD-PD), and examined glycosylation of native fibrinogen and its subunits by lectin-based microarray and lectin blotting. Compared to healthy controls, fibrinogen from patients had increased levels of A2BG2 and decreased levels of FA2 glycan. The distribution of glycans on individual chains was also affected, with the γ chain, responsible for physiological functions of fibrinogen (such as coagulation and platelet aggregation), being most prone to these alterations. Increased levels of multi-antennary N-glycans in ESRD-PD patients were also associated with the type of dialysis solutions, whereas an increase in the fucosylation levels was strongly related to the peritoneal membrane damage. Consequently, investigation of fibrinogen glycans can offer better insight into fibrinogen-related complications observed in ESRD-PD patients and, additionally, contribute to prognosis, choice of personalised therapy, determination of peritoneal membrane damage, and the length of utilization of peritoneum for dialysis.

The impact of asthma on quality of life and symptoms in patients with chronic rhinosinusitis.

Objective: The study aims to evaluate how asthma influences on clinical symptoms, imaging scores and HRQL in CRS patients.Methods: The study enrolled CRS patients and collected data about asthma status, clinical symptoms, allergic sensitization, computed tomography (CT) and 22-item SinoNasal Outcome questionnaire (SNOT-22). Matching pairs of asthmatic and non-asthmatic CRS patients were defined based on age, gender and nasal polyp presence. The difference between pairs in clinical symptoms, CT and SNOT-22 was then analyzed. The study enrolled mild to moderate asthma patients.Results: From 250 CRS patients 65 (26%) had asthma. We found 60 CRS asthma and CRS non-asthma pairs based on age, gender and nasal polyp presence. There was no difference in total SNOT-22 score between asthma (46.5) and non-asthma (43.5) CRS groups (p < .357). There were more patients with allergy positive medical history in asthma group (66.1%) when we stratified for CRS phenotypes, gender and age. Comparing visual analogue scale (VAS) scores for clinical symptoms, smell (p < .013) was the only symptom significantly worse in CRS asthma group. Although there was no difference in Lund-Mackay score, there was a slightly higher osteitis score in CRS asthma group (5.21 vs. 3.45; p = .059).Conclusion: CRS patients with asthma have significantly worse impairment of smell and taste when compared to non-asthmatic CRS patients. This is the only significant difference which is independent of nasal polyp presence, gender, age and allergy.

Characterisation of the binding of dihydro-alpha-lipoic acid to fibrinogen and the effects on fibrinogen oxidation and fibrin formation.

A reduced form of the alpha-lipoic acid, dihydro-alpha-lipoic acid (DHLA) is a potent, naturally occurring antioxidant which can be consumed as food constituent or as supplement at doses up to 600 mg/day. DHLA has inhibitory effect on coagulation as it can reduce concentrations of some coagulation factors. In this study, a direct interaction between DHLA and fibrinogen, the main protein in coagulation, is described. Binding constant for DHLA/fibrinogen complex is of moderate strength (104) and interaction probably occurs in D regions of fibrinogen, as shown by docking simulations. Fibrinogen stability remains the same with only marginal structural changes in its secondary structure favouring more ordered molecular organisation upon DHLA binding. Fibrinogen with bound DHLA forms fibrin with thicker fibers, as measured by coagulation assay and is protected from oxidation to certain extent. Obtained results support beneficial effects of DHLA on fibrinogen and consequently on coagulation process, suggesting that DHLA supplementation may be indicated for persons with an increased risk of developing thrombotic complications, particularly those whose fibrin is characterised by increased oxidative modification and formation of thinner and less porous fibers. Also, DHLA in complex with fibrinogen can be located at site of injury where it may exert antioxidant effects.

Mixed Type Haemangioma of the Inferior Turbinate: A Rare Cause of Epistaxis.

Haemangiomas of the nasal cavity are rare benign tumours which usually arise in the Kiesselbach triangle of the septum. Mostly they are seen in young population with peak age 20 years. Epistaxis is the most common symptom in these patients. We present a case of a 62-year-old woman with recurrent epistaxis. On examination she had had an obstruction of both nasal cavities. Computed tomography imaging demonstrated a well-defined tumour originating from the posterior tip of the right inferior turbinate, passing into the nasopharynx. The tumour was managed via endoscopic endonasal approach. The histological analysis revealed a tumour tissue with the appearance of a cavernous haemangioma as well as capillary haemangioma. A focus of intravascular endothelial papillary hyperplasia was also observed. In patients with endonasal benign tumours choice of surgical approach depends on the exact location of the tumour and suspected pathology. The transnasal endoscopic approach and bipolar cautery resection enable adequate exposure and visualization of the tumour, control of bleeding and complete removal of the tumour.